Bone is the body's framework. Bone contains calcium (Ca2+) and plays an important role in maintaining the calcium level in blood. To this end, the growth of bone is a metabolic balance between the activity of osteoblasts and osteoclasts in the bone remodeling cycle.
When the balance between bone absorption and bone formation is disrupted, the amount of bone tissue replaced by osteoblasts fails to match that absorbed by osteoclasts, thus leading to osteoporosis, a common condition which result in the loss of bone density or bone mass. This disease frequently occurs in middle-aged or elderly women.
Osteoporosis is a metabolic bone disease, which results from a disturbance in the normal bone remodeling, tilting the balance between bone resorption and formation, thus resulting in bone loss and fractures after mineral flux. Bone is the dynamic structures, in which the osteoblast bone formation and osteoclast bone resorption are continuously occurred.
Previous studies focused on the metabolisms of bone inorganic materials like calcium and inorganic phosphorus. Such studies did not provide sufficient findings regarding the mechanisms of osteoporosis.
Although bisphosphonates (alendronate, etidronate etc.), hormones (raloxifen), Vitamin D, Calcitonin, calcium agents, etc. have been used as anti-osteoporetic agents, they have some adverse side effect or defects. Bisphosphontes show low pharmacokinetic profiles, are difficult to dose and may induce esophagitis. Hormone agents must be administered continuously. Also, in case of long term therapy, severe side effects such as breast cancer, gallstones and embolism may be induced. Vitamin D agents are expensive and show little efficacy in treating estrogen-deficient osteoporetic patients. Calcitonin is also very expensive and difficult to administrate. Calcium has few adverse side effects, but its effects is restricted to the prevention of osteoporosis not the treatment of it.
Osteoporosis requires long term therapy, thus it is necessary for the development of new drugs to not include the above-mentioned adverse effects.
A bone fracture is a break or crack in a bone, with complete or incomplete disruption of the continuity of a bone, epiphyseal plate or articular surface. A bone fracture is caused mostly by some type of trauma to a bone. This trauma might occur as a result of a motor vehicle accident, workplace accident, physical abuse, repetitive stress such as exercise, heavy lifting, etc. According to fracture line (line along epiphyseal ends generated upon fracture), bone fractures are classified into fissured fractures, greenstick fractures, transverse fractures, oblique fractures, spiral fractures, segmental fractures, comminuted fractures, avulsion fractures, compression fractures, depressed fractures, etc.
It is common for bone fractures to injure blood, thus resulting in partial hemorrhage and blood clots. In addition, the bone matrix around a fracture region breaks down or ruptures, with the death of osteocytes. During a fracture healing process, hence, the blood clots and the injured osteocytes and bone matrix are removed by macrophages while osteoprogenitor cells of the perilsteum and endosteum around the fracture region actively proliferate to form cellular tissue around the fracture region and are then integrated with the fracture region. In the connective tissue of the fracture region, either a bone tissue arises by endochondral ossification from a small cartilage fragment or an immature bone is formed by intramembranous ossification. Accordingly, intramembranous ossification from mesenchymal tissue and endochondral ossification are observed concurrently in the connective tissue of a fracture region. The trabecula of the immature bone irregularly formed in this way temporarily connects ends of the fractured bone fragments, resulting in the formation of a bony callus. The woven bone of the bony callus formed in the fracture region is gradually resorbed as the healing process progresses, and undergoes rearrangement resulting in the development of lamellar bone.
The healing process for fracture is largely divided into three phases: inflammatory phase, bone reparative phase, and remodeling phase.
In the inflammatory phase, inflammatory responses occur since tissues around a fracture region are injured and hematoma fills the fracture gap.
In the bone reparative phase, the hematoma is removed from the fracture gap and substituted with granulation tissue while soft callus is formed. According to the osteogenesis mechanism, two processes proceed concurrently: endochondral ossification, in which the soft callus is remodeled into hard callus, and fibrous/intramembranous ossification, in which a new bone is formed by osteogenic cells.
In the remodeling phase, newly formed bone tissue is extended over a long period of time by the orchestrated action of osteoclastic bone resorption and osteoblastic bone formation, with the correction of bone distortions and the reinforcement of bone defects.
During the remodeling phase, patients with a bone fracture conduct their lives without great difficulty because the newly formed bone has become hard to some extent, but the nascent bone tissue in the reparative phase is not hard enough for patients to live their daily lives without difficulty. In addition, the reparative phase is long. Thus, it is clinically important for a fracture curative to have the function of shortening the reparative phase as well as regenerating a fractured bone into a complete bone by promoting the complex fracture healing process.
There are various promoters for fracture healing. Peptides having physiologically active functions, such as bone morphogenic proteins (BMPs) and transforming growth factors (TGFs), are found to be involved in the fracture healing process (Proc. Natl. Acad. Sci., USA, vol. 87, pp. 2220-2224 (1989)). Also, it has been studied that an increase in intracellular cyclic AMP level by use of a phosphodiesterase (PDE) inhibitor can lead to an increase in bone mass. For example, it is reported that mice, into which the general PDE inhibitor pentoxipylline or the selective PDE4 inhibitor rolipram had been subcutaneously injected every day, were observed to have the vertebrate and femur increased in bone mineral density, and showed hyperplasia of cortical bones (Bone, vol. 27, 6th edition, pp. 811-817 (2000)).
As mentioned above, attention has long been paid to osteogenesis and fracture healing, and extensive studies on fracture healing processes have been conducted from various points of view, including genetic factors, adolescent influence, hematopoietic effect, fixture effect, bone grafts, other healing promoting factors, etc. (Kawamura, M and Urist M R., Clin. Orthop., 236, 240-248, 1988).
Fracture healing requires a significant period of time and elderly patients with osteoporosis tend to suffer more from bone fractures. Falling short of the expectation of usefulness in fracture healing, currently available therapeutic agents for the treatment of osteoporosis, such as calcium, estrogen, calcitonin, active vitamin D, biphosphonate, etc., are found only to lower the risk of fracture by obstructing the decrease of bone density, and have no function of joining fractured bones or generating bone tissues. The pathogenic mechanism of osteoporosis can be explained by a subtle bone matrix resulting from long maintenance of negative bone homeostasis due to genetic or constitutional predispositions, stagnant osteogenesis with normal bone resorption, and increased bone resorption with normal osteogenesis. Osteoporosis agents are, therefore, ineffective for the treatment of bone fractures because the healing mechanism is quite different between fractures and osteoporosis.
Therefore, there is an urgent need for a bone fracture curative agent that has great therapeutic effect on bone fractures, regardless of association with osteoporosis
As diverse pathologies associated with environmental pollution, stress, living environments, etc., an allergic inflammatory disease has increased. Allergic inflammatory disease is attributed to abnormality in the immune system where the nasal or bronchial mucosa or skin is hypersensitive to external allergens. Basic causes of allergy include nutrition imbalance, stress, extravasated blood, etc., with the major cause being nutrition imbalance.
Depending on the site where immune responses occur against exogenous allergens, allergic inflammatory disease is represented as various symptoms including allergic rhinitis, asthma, atopic dermatitis, etc. In addition, allergic conjunctivitis, allergic dermatitis, contact dermatitis, urticaria, etc. are within the scope of allergic inflammatory diseases. Since these symptoms, although very diverse, are common in the pathology based on the hypersensitivity to externally introduced matter, a suppressant of excessive immune responses can be prescribed for all of them.
Asthma, representative of allergies, is a chronic inflammatory disease occurring in the respiratory organ, especially, the lungs and the bronchi. When patients with asthma take drugs or excessive exercise or inhale contaminated and/or cold air, their respiratory organs, especially, upper respiratory organs increase in responsiveness. This hyper-responsiveness is associated with the airflow obstruction in the airway, that is, airway obstruction or tracheal stenosis, but is readily alleviated using a bronchodilator. Included in the consensus characteristics of asthma, hyper-responsiveness to indoor and/or outdoor allergens and airway contraction are known to be mediated by mast cells and eosinophil IgE (Beasley et al., Am. Rev. Respir. Dis., 129, 806-817, 1989).
Asthma is accompanied by the allergic hyper-responsiveness mainly in the bronchia and the lungs. Particularly, the air passage becomes clogged by the proliferation of mucous cells and the inflammation of epithelial connective tissues in the bronchia. Alsom the lungs are known to show similar histological behaviors. The pathology of asthma, although not yet clearly revealed thus far, is reported to be featured by airway stenosis, edema, mucus secretion, inflammatory cell infiltration, etc. In the mechanism of a typical exogenous asthma, when an antigen is introduced into the airway, B cells produce antigen specific antibodies IgE and IgG in cooperation with macrophages and helper T-cells. These antigen specific antibodies bind to receptors on the surfaces of mast cells and basophils, which are then activated upon re-exposure to the same antigen so as to release various cytokines and mediators of allergy/inflammation, including histamine, prostaglandin D2, slow reacting substances (leukotriene C4, D4), etc. out of the cells. Due to these cytokines and mediators, when exposed to aeroallergen, patients with asthma exhibit an early asthma response characterized by a rapid airway constriction over a period of seconds to minutes and apparent recovery within 30 to 60 min from the constriction. Then, the mediators secreted from mast cells and the cytokines secreted from macrophages, mast cells and helper T-cells proliferate and activate inflammatory cells, including eosinophils, to exhibit a late asthmatic response in which bronchoconstriction, mucus secretion and inflammatory cell infiltration begin 3 to 4 hours and peak 4 to 18 hours after exposure to aeroallergens (Robertson et al., J. Allergy Clin. Immunol., 54, 244-257, 1974).
Currently available therapeutic agents for the treatment of asthma include beta 2-adreno receptor agonists, which dilate airway smooth muscles and effectively, inhibit the secretion of hyperresponsiveness mediators from mast cells, adrenal cortical hormones, which exhibit an immunosuppressive effect, and disodium cromoglycate and nedocromil sodium, both known to inhibit both the early and the late asthma response. However, beta 2-adreno receptor antagonists show the treatment effect only for a short period of time and allow the ready recurrence of the disease. Adrenal cortical hormones have fragmentary treatment effects, with the concomitance of serious side effects upon long-term dosage.
Leading to the present invention, intensive and thorough study on osteoporosis, bone fractures and allergic inflammatory diseases conducted by the present inventors, resulted in the finding that novel benzamidine derivatives have effects on suppressing the osteoclastic bone resorption and inhibiting the decrease of bone mass in animal models, indication the compounds are useful in the prevention and treatment of osteoporosis; healing bone fractures; and treating and preventing allergic inflammatory disease.